The novel compounds described herein are structurally related to the known naturally occurring substance, melatonin. Melatonin, 5-methoxy-N-acetyltryptamine, is a hormone produced primarily by the pineal gland. The synthesis and secretion of melatonin exhibit a circadian rhythm that changes with the seasons and with age, e.g., pubescence and senescence. The rhythm is the result of both endogenous mechanisms and environmental cues, most notably, the exposure of organisms to light, which inhibits melatonin synthesis and secretion. Thus, melatonin levels are high at night and low during the day. There is very strong evidence that melatonin is important for the regulation of a variety of neural and endocrine functions, especially those that exhibit circadian and circannual rhythmicity.
Novel compounds related to melatonin, but with pharmacological or pharmacokinetic profiles different from melatonin, are likely to be important new pharmaceuticals. For examples, see U.S. Pat. Nos. 5,151,446 of Horn et al., 5,194,614 of Adrieux et al. and 5,276,051 of Lesieur et al. There is evidence suggesting both melatonin agonists and antagonists would be of potential therapeutic use.
Melatonin has been implicated in many human disorders. Some disorders are known to be linked to chronobiologic abnormalities. Melatonin has been administered to re-synchronize circadian rhythms that are out of phase with the local environmental cues; i.e. chronobiological therapy. For example, sleep/wake disorders associated with rapid crossing of time zones (jet lag), changes in work shifts, or those experienced by blind people can be treated with melatonin or melatonin analogs (see U.S. Pat. Nos. 4,600,723 and 4,665,086 of Short et al., and 5,242,941 of Lewy et al.).
However, it appears that melatonin also has direct sedative/hypnotic properties in normal human subjects. Several groups of investigators have demonstrated sleepiness following intravenous, oral and intranasal administration of melatonin to humans (e.g. Waldhauser et al., Psychopharmacology, 100: 222-226, 1990; Vollrath et al., Bioscience 29:327-329, 1981; Dollins et al., Proc. Natl. Acad. Sci., 99:1824-1828, 1994). It appears that melatonin does not have the side-effect liability associated with current hypnotics, e.g. amnesia, "hangover", dependence and tolerance.
Sedative/hypnotic agents often exhibit other useful properties, such as anxiolytic and antiseizure actions. Melatonin has been demonstrated in a number of rodent experimental paradigms to have both anxiolytic (Golus and King, Pharmacol. Biochem. Behav. 15:883-885, 1981; Guardiola et al., Pharmacol. Biochem Behav. 41:405-408, 1992, Naranjo-Rodriguez et al., Soc. Neurosci. Abst. 18:1167, 1992; Golombek et al., Eur. J. Pharmacol. 237:231-236, 1993) and antiseizure activity (Brailowsky, Electroencephalo. Clin. Neurophysiol. 41:314-319, 1976; Fariello et al., Neurology 27:567-570, 1977, Rudeen et al., Epilepsia 21:149-154, 1980; Sugden, J. Pharmacol. Exp. Ther. 227:587-591, 1983; Golombek et al., Eur. J. Pharmacol. 210:253-258, 1992). In humans with panic disorder, a severe anxiety problem, melatonin secretion is abnormal (Mcintyre et al., Am. J. Psychiat. 147:462-464, 1990).
Melatonin may play a role in other psychiatric conditions, particularly depression, but also mania and schizophrenia (see Dubocovich "Antidepressant Agents", U.S. Pat. No. 5,093,352; Miles and Philbrick, Biol. Psychiatry 23:405-425, 1988; Sandyk and Kay, Schizophr. Bull. 16:653-662, 1990). In some instances, psychiatric disorders may have underlying chronobiologic etiologies (e.g. seasonal affective disorder) and are definite candidates for melatonin therapy.
Melatonin is involved in the regulation of circadian and circannual changes in body temperature. Administration of exogenous melatonin to humans lowers core body temperature (Strassman et al., J. Appl. Physiol. 71:2178-2182, 1991; Cagnacci et al., J. Clin. Endocrinol. Metab. 75:447-452, 1992). Melatonin may also possess analgesic properties (Sugden, J. Pharmacol. Exp. Ther. 227:587-591, 1983). Therefore, melatonin-like compounds may be useful as an alternative to non-steroidal anti-inflammatory, anti-pyretic drugs, such as aspirin, acetaminophen and ibuprofen.
It is known that melatonin levels decrease with advancing age (Sack et al., J. Pineal Res. 4:379-388, 1986; Waldhauser et al., J. Clin. Endocrinol. Metab. 66:648-652, 1988; Van Coevorden et al., Am. J. Physiol. 260:E651-661, 1991) which may contribute to some disorders. Neurodegenerative diseases often associated with aging, such as Alzheimer's and Parkinson's diseases, may be treated with melatonergic compounds (Maurizi, Med. Hypotheses 31:233-242, 1990; Sandyk, Int. J. Neurosci. 50:37-53, 1990; Skene et al., Brain Res. 528:170-174, 1990). Sleep disorders in the elderly recently have been shown to respond to melatonin treatment (Haimov and Lavie, unpublished findings). Even osteoporosis may have a melatoninergic component (Sandyk et al., Int. J. Neurosci. 62:215-225, 1992). In fact, melatonin has been suggested to be an anti-aging, anti-stress hormone (Armstrong and Redman, Med. Hypotheses 34:300-309, 1991; Reiter, Bioessays 14:169-175, 1992). This may be due to its action as a free radical scavenger (Poeggeler et al., J. Pineal Res. 14:151-168, 1993) or its interaction with the immune system (Maestroni and Conti, J. Neuroimmun. 28:167-176, 1990; Fraschini et al., Acta. Oncol. 29:775-776 1990; Guerrero and Reiter, Endocr. Res. 18:91-113, 1992).
Related to the above, are the findings that melatonin has oncostatic properties in a variety of cancers, the most studied being its effects on estrogen receptor positive breast cancers (Blask and Hill, J. Neural Transm. Suppl. 21:433-449, 1986; Gonzalez et al. Melanoma Res. 1:237-243, 1991; Lisoni et al., Eur. J. Cancer 29A:185-189, 1993; Shellard et al., Br. J. Cancer 60:288-290, 1989; Philo and Berkowitz, J. Urol. 139:1099-1102, 1988; see U.S. Pat. Nos. 5,196,435 of Clemens et al. and 5,272,141 of Fraschini et al.). It is also possible that melatonin has antiproliferative effects on non-cancerous cells as well, and may be of use to treat benign tumors and proliferative diseases such as psoriasis.
A major portion of research on melatonin has been devoted to studying its effects on reproduction, particularly in seasonally-breeding species (such as hamsters and sheep), in which melatonin is known to regulate fertility and puberty, hibernation, and coat color. These effects have obvious significance for animal husbandry use. Reproductive endocrine uses in humans for melatonin include: contraceptive and fertility agents, treatment for precocious puberty, treatment for premenstrual syndrome and hyperprolactinemia (Fevre et al., J. Clin. Endocrinol. Metab. 47:1383-1386, 1978; Parry et al., Am. J. Psychiatry 144:762-766, 1987; Waldhauser et al., J. Clin. Endocrinol. Metab. 73:793-796, 1991; Bispink et al., J. Pineal Res. 8:97-106, 1990; Cagnacci et al., J. Clin. Endocrinol. Metab. 73:210-220, 1991; Voordouw et al., J. Clin. Endocrinol. Metab. 74:107-108, 1992; see U.S. Pat. Nos. 4,855,305 and 4,945,103 of Cohen et al., and 5,272,141 of Fraschini et al.) It is likely that melatonin compounds may also be useful in other endocrine conditions, particularly those involving growth hormone (Cramer et al., Arzneim.-Forsch. 26:1076-1078, 1976; Wright et al., Clin. Endocrinol. 24:375-382, 1986; Paccotti et al., Chronobiologica 15:279-288, 1988; Valcavi et al., Clin. Endocrinol. 39:193-199, 1993).
In addition to the pineal gland, the eye also synthesizes melatonin. Recently melatonin has been implicated in the control of intraocular pressure and may be of use in glaucoma (Samples et al., Curr. Eye Res. 7:649-653, 1988; Rhode et al., Ophthalmic Res. 25:10-15, 1993). Research on the function of melatonin in the eye may uncover additional novel therapeutic uses.
It is clear that there exists a broad range of therapeutic uses for melatonin. Accordingly, it is of continuing interest to identify novel compounds that interact with melatonergic systems as potential therapeutic agents. These compounds may offer improved pharmacokinetic (i.e. longer duration, greater potency) and/or pharmacodynamic (i.e. greater efficacy) actions to those of melatonin. This invention addresses the need for more therapeutically effective compounds than melatonin.
Citation or identification of any reference in this section of this application shall not be construed as an admission that such reference is available as prior art to the present invention.